Phase II SBIR: WHI-07: A Novel Dual-Function Microbicide

II 期 SBIR：WHI-07：一种新型双功能杀菌剂

基本信息

批准号：
6952352
负责人：
OSMOND J D'CRUZ
金额：
$ 37.87万
依托单位：
PARADIGM PHARMACEUTICALS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-08-01 至 2007-08-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The current pandemic of sexually transmitted HIV/AIDS has created an urgent need for a new type of microbicide: one that is both a spermicide and a virucide. The goal of the proposed Phase II work is to further develop WHI-07, a novel 5-bromo 6-methoxy aryl phosphoramidate derivative of 3'-azido-3'-deoxythymidine (zidovudine, ZDV/AZT) as a dual-function anti-HlV microbicide. WHI-07 was rationally designed to bypass the thymidine kinase dependency of ZDV activation in genital tract secretions. WHI-07 was formulated via a nontoxic gel-microemulsion for intravaginal use as a potential candidate anti-HIV spermicide. The in vivo efficacy as well as safety studies of WHI-07 have included: (i) vaginal as well as rectal microbicide efficacy studies in the feline immunodeficiency vires (FIV)/domestic cat model for AIDS; (ii) in vivo retention of anti-HIV activity in the nonhuman primate; (iii) vaginal contraceptive efficacy studies in rabbits; (iv) single- and/or multiple-dose toxicity studies in mice, rabbits, cats as well as monkey; (v) mucosal, reproductive, and developmental toxicity studies in mice and rabbits; (vi) cytotoxicity, mutagenicity, and genotoxicy tests using human and yeast cells; and (vii) long-term carcinogenicity studies in mice. Under Phase I proposal we tested: (i) the ability of WHI-07 to prevent transvaginal as well as transrectal transmission of FIV in domestic cats as a model for sexual transmission of HIV; and (ii) determined the lack of developmental toxicity of WHI-07 in the rabbit model. Our discovery that WHI-07 either alone or in combination with a bis(cyclopentadienyl) vanadium(IV) complex, vanadocene dithiocarbamate (VDDTC), effectively protected domestic cats from systemic FIV infection via genital exposure to mucosally transmissible FIV-infected feline T cells has clinical potential for the development of a dual-function anti-HIV microbicide for sexually active women. Under Phase II funding, we propose to test the in vivo antiretroviral and contraceptive efficacies as well as safety studies of WHI-07 plus VDDTC gel-microemulsion to further explore the utility of WHI-07 either alone and in combination with VDDTC as a vaginal spermicidal anti-HIV microbicide in the clinical setting. We hypothesize that the combination of these two active agents with different mechanisms of action will potentially improve efficacy and duration of dual-protection when compared to WHI-07 alone while maintaining an adequate safety profile. The goals of Phase II study are (i) to examine the optimum microbicide activity of WHI-07 plus VDDTC gel-microemulsion versus WHI-07 alone to prevent systemic FIV infection of domestic cats from transvaginal and transrectal challenge with FIV-infected cells; (ii) to evaluate the in vivo contraceptive efficacy of WHI-07 plus VDDTC gel-microemulsion in rabbits; (iii) to assess the mucosal safety and developmental toxicity of WHI-07 plus VDDTC gel-microemulsion in rabbits; and (iv) to assess the stability WHI-07 plus VDDTC in-gel-microemulsion. The proposed Phase II work will complement and enhance the discovery and preclinical development of safe and effective dual-function microbicides at Paradigm Pharmaceuticals that may provide the basis for a new strategy to prevent the sexual transmission of HIV while providing effective fertility control for women.

描述（由申请人提供）：当前性传播的艾滋病毒/艾滋病的大流行迫切需要一种新型的杀菌剂：一种既是杀虫剂又是病毒蛋白。拟议的II期工作的目的是进一步开发WHI-07，这是一种新型的5-溴6-甲氧基芳基磷化酰胺衍生物，该衍生物是3'-azido-3'-脱氧胸苷（Zidovudine，ZDV/AZT）作为双功能抗HLV杀菌皮菌件。 WHI-07的理性设计绕过生殖道分泌物中ZDV激活的胸苷激酶依赖性。 WHI-07是通过无毒的凝胶微乳液制定的，用于阴道内用作潜在的候选抗HIV杀伤物菌素。体内疗效以及WHI-07的安全性研究包括：（i）猫免疫缺陷病毒（FIV）/艾滋病模型中的阴道和直肠菌心疗效研究；（ii）非人类灵长类动物中抗HIV活性的体内保留；（iii）兔子中的阴道避孕功效研究；（iv）小鼠，兔子，猫以及猴子的单剂量毒性研究；（v）小鼠和兔子的粘膜，生殖和发育毒性研究；（VI）使用人和酵母细胞进行细胞毒性，诱变性和基因毒性测试；（vii）小鼠的长期致癌性研究。根据第一阶段的建议，我们测试了：（i）WHI-07防止家庭猫中FIV的经阴道和直肠直肠传播的能力，作为HIV性传播的模型；（ii）确定了兔模型中WHI-07缺乏发育毒性。 Our discovery that WHI-07 either alone or in combination with a bis(cyclopentadienyl) vanadium(IV) complex, vanadocene dithiocarbamate (VDDTC), effectively protected domestic cats from systemic FIV infection via genital exposure to mucosally transmissible FIV-infected feline T cells has clinical potential for the development of a dual-function anti-HIV microbicide for sexually活跃的女性。在第二阶段的资金下，我们建议测试体内抗逆转录病毒和避孕功能以及对WHI-07加上VDDTC凝胶 - 微乳液的安全性研究，以进一步探索单独的WHI-07的实用性，并与VDDTC结合使用VDDTC作为阴道的抗抗激素抗抗激素抗抗激素Microbicide临床设置。我们假设这两种活性药物与不同的作用机制的组合将有可能提高双重保护的功效和持续时间，而与单独的WHI-07相比，同时保持了足够的安全性。 II阶段研究的目标是（i）检查whi-07加上VDDTC凝胶 - 微乳液的最佳杀菌活性与仅WHI-07的最佳杀菌活性，以防止与FIV感染的细胞受到经阴道和经阴道直肠挑战的全身性FIV感染；（ii）评估WHI-07加上VDDTC凝胶 - 微乳液的体内避孕功效；（iii）评估兔子中whi-07加VDDTC凝胶 - 微乳液的粘膜安全性和发育毒性；（iv）评估稳定性whi-07加VDDTC内 - 凝胶微乳液。拟议的第二阶段工作将补充和增强在范式药物范式药物的安全有效双功能杀菌剂的发现和临床前开发，这可能为防止艾滋病毒的性传播的新策略提供基础，同时为女性提供有效的生育能力。